U.S. patent application number 10/275252 was filed with the patent office on 2003-09-11 for process for cross-linking an acrylic polymer or copolymer or an acrylic derivatives of a copolymer and the cross-linked acrylic polymer thereby obtained.
Invention is credited to Balestrieri, Gerardo, Protopapa, Carmelo.
Application Number | 20030171509 10/275252 |
Document ID | / |
Family ID | 11438935 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030171509 |
Kind Code |
A1 |
Balestrieri, Gerardo ; et
al. |
September 11, 2003 |
Process for cross-linking an acrylic polymer or copolymer or an
acrylic derivatives of a copolymer and the cross-linked acrylic
polymer thereby obtained
Abstract
The invention relates to a process for cross-linking an acrylic
polymer and the acrylic polymer made using this process.
Inventors: |
Balestrieri, Gerardo;
(Milano, IT) ; Protopapa, Carmelo; (Bologna,
IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Family ID: |
11438935 |
Appl. No.: |
10/275252 |
Filed: |
November 7, 2002 |
PCT Filed: |
December 24, 2001 |
PCT NO: |
PCT/IB01/02721 |
Current U.S.
Class: |
526/90 ; 524/827;
526/303.1 |
Current CPC
Class: |
C08F 220/56
20130101 |
Class at
Publication: |
526/90 ;
526/303.1; 524/827 |
International
Class: |
C08F 004/06 |
Claims
1. A process for preparing a cross-linked acrylic polymer from
water-soluble acrylamide monomers comprising the following steps:
preparing an aqueous polymerizing solution comprising the
acrylamide monomer and catalyzing agents; polymerizing the monomers
present in the polymerizing solution by agitating and heating the
polymerizing solution; the process being characterised in that the
polymerization step is conducted in the presence of gaseous oxygen
to obtain a cross-linked acrylic polymer.
2. The process according to claim 1 wherein the polymerizing
solution is saturated with gaseous oxygen.
3. The process according to claim 2, wherein the oxygen is bubbled
through the polymerizing solution for a length of time varying from
1 to 24 hours at a temperature between 30 and 60.degree. C.
4. The process according to one or more of the foregoing claims,
wherein, after the polymerization step, the polymer is subjected to
a further step of washing in aqueous medium at a temperature from
80 to 100.degree. C. for a length of time varying from 3 to 5
hours.
5. The process according to claim 4, wherein, after the washing
step, the polymer is held at a temperature between 110 and
130.degree. C. for a length of time varying from 1 to 6 hours.
6. The process according to claim 1, wherein the polymerization of
the monomers is performed at a temperature between 30 and
80.degree. C.
7. The process according to claim 7, wherein the polymerization of
the monomers is performed for a length of time varying from 1 to 24
hours.
8. The process according to one or more of the foregoing claims,
wherein the aqueous polymerizing solution comprises the acrylamide
monomer and one or more other monomers selected from
N,N'-methylene-bits-acrylamide and
N,N'-ethylene-bis-acrylamide.
9. The process according to one or more of the foregoing claims,
wherein the polymerizing solution further comprises
ethylene-bis(oxyethylene nitrilo)-tetracetic acid.
10. The process according to claim 1, wherein the polymerization
step is performed in the presence of metal salts having a metal
cation selected from aluminium, zirconium, and titanium.
11. A cross-linked acrylic polymer obtainable using the process
according to one or more of the foregoing claims from 1 to 10.
12. The acrylic polymer according to claim 11 for use as a filling
material in cosmetic and reconstructive plastic surgery.
Description
TECHNICAL FIELD
[0001] The present invention relates to a process for cross-linking
an acrylic polymer or copolymer or an acrylic derivative of a
copolymer and the cross-linked acrylic polymer thereby
obtained.
BACKGROUND ART
[0002] The use of mini-invasive techniques is well-known in modern
cosmetic and reconstructive plastic surgery. Many of these
techniques involve the use of a fillers.
[0003] The fillers known today have many advantages but also
present major application limits. For example, natural products
(such as collagen and hyaluronic acid) are rapidly reabsorbed.
Methacrylates are reabsorbed more slowly but do not possess an
adequate degree of biocompatibility. Common polyacrylamide is
highly biocompatible but does not possess sufficient chemical and
physical stability and thus is not suitable for use in large
quantities to fill large spaces.
[0004] The need therefore remains for a material that possesses all
the properties expected of a good filler. Numerous methods of
polymer cross-linking are known. These differ according to the type
of polymer to be cross-linked and the type of cross-linking
required.
[0005] The cross-linking of a polymer can be accomplished by
chemically bonding monomers, polymer fragments or parts of polymer
chains to the molecular chains of the polymer. For the
cross-linking reaction of a polymer, several types of catalysts or
catalytic systems are used. The nature of the catalyst depends on
the type of cross-linking reaction to be achieved in the molecular
chains of the polymer.
[0006] The catalysts may be chosen from compounds having peroxide
groups, silane products or nitrate compounds. Alternatively,
[0007] polymerization (and cross linking) can in some cases be
initiated by electron beams.
[0008] Well-known examples of cross-linking reactions are the
reactions of sulphur with rubber and a large number of elastomers
(vulcanization) and the reaction of glycol, maleic acid and styrene
to obtain reinforced polyesters.
[0009] In the field of cross-linked acrylic polymers obtained by a
polymerizing reaction between acrylic monomers or derivatives
thereof, the need is felt for a process in which the cross-linking
of the polymer occurs in the reaction medium during the monomer
polymerizing stage.
[0010] In particular, there remains a need for a cross-linking
system capable of reacting during the monomer polymerizing
stage.
[0011] The present invention has for one of its objects to provide
a process for preparing a cross-linked acrylic polymer, in the form
of a hydrogel, from water-soluble acrylamide monomers and catalysts
whose cross-linking is subject to reaction during and after the
polymerization stage.
[0012] Another object of the invention is to provide a
water-insoluble insoluble, cross-linked acrylic polymer made using
the process according to the invention.
[0013] These and other objects, which will become apparent in the
detailed description that follows. have been attained by the
Applicant using a process in which the cross-linking of a polymer
or of a copolymer is accomplished by reacting the water-soluble
amide monomers in the presence of molecular oxygen during the
polymerization stage.
DISCLOSURE OF THE INVENTION
[0014] The first object of the invention is accomplished by
providing a process for preparing a cross-linked acrylic polymer,
as described in the independent claim below.
[0015] The second object of the invention is accomplished by
providing a cross-linked acrylic polymer, as described in the
independent claim below.
[0016] Other preferred embodiments of the invention are described
in the dependent claims.
[0017] Further technical characteristics of the invention appear in
the detailed description below, from which the advantages of the
invention will become evident.
[0018] The process for preparing a cross-linked acrylic polymer
according to this invention comprises a first step of preparing an
aqueous polymerizing solution comprising the acrylamide monomer,
catalyzing agents and, possibly, also a chelating agent such as for
example ethylene-bis(oxyethylene nitrilo)-tetracetic acid.
[0019] In addition to acrylamide, the polymerizing solution
preferably includes other monomers, chosen from
N,N'-methylene-bis-acrylamide and N,N'-ethylene-bis-acrylamide. In
this case, the polymerizing process according to the present
invention provides an acrylic copolymer or an acrylic derivative of
a copolymer.
[0020] Preferably the aqueous polymerizing solution comprises the
acrylamide monomer, a derivative of it such as methylolacrylamide,
one or more monomers chosen from N,N'-methylene-bis-acrylamide and
N,N'-ethylene-bis-acrylamide, catalyzing agents and, possibly, a
chelating agent such as ethylene-bis(oxyethylene
nitrilo)-tetracetic acid.
[0021] The polymer, prepared from amide monomers, takes the form of
a hydrogel with imide-amide cross links which can be schematically
represented as follows: 1
[0022] Under certain conditions, ammonia may be released.
[0023] The quantities are expressed in terms of weight and are
preferably in the range from 2 to 7% of acrylamide, preferably 3 to
5%, from 0.2 to 4% of N,N'-methylene-bis-acrylamide, and from 0.1
to 4% of N,N'-ethylene-bis-acrylamide.
[0024] Preferably the catalyst is ammonium persulphate or hydrogen
peroxide or any other catalyst normally used in redox polymerizing
reactions.
[0025] The polymerizing solution is an aqueous solution made with
distilled water, preferably twice-distilled apyrogenic water.
[0026] The process according to the invention involves a subsequent
step of polymerizing the monomers present in the polymerizing
solution.
[0027] Polymerization is achieved by agitating and heating the
polymerizing solution to a temperature of between 30 and 80.degree.
C.
[0028] The polymerizing reaction lasts from 1 to 48 hours,
preferably 1 to 24 hours and, better still, 4 to 16 hours.
[0029] The polymerizing step must be performed with gaseous oxygen.
The presence of gaseous oxygen during the polymerization reaction
makes it possible to achieve cross-linking of the acrylic polymer
as described below. The presence of gaseous oxygen during the
reaction modulates polymerization (including cross-linking and
co-polymerization) to obtain a hydrogel with a different molecular
weight.
[0030] Preferably, the polymerizing solution is saturated with
gaseous oxygen.
[0031] Preferably, the oxygen is bubbled through the polymerizing
solution for a length of time varying from 1 to 24 hours at a
temperature of between 30 and 80.degree. C.
[0032] The polymerization process can be performed using metal
salts containing metal cations, such as aluminium, zirconium and
titanium, having the valencies suitable for further chelating
certain intramolecular structures.
[0033] Advantageously, the polymerization step is followed by a
step of washing the polymer in aqueous medium at a temperature of
80 to 100.degree. C. for a length of time ranging from 1 to 5
hours, preferably from 3 to 4 hours.
[0034] Advantageously, after the washing step, the polymer is
maintained at a temperature of between 110 and 130.degree. C. for a
length of time varying from 0.5 to 6 hours.
[0035] Alternatively, the aqueous polymerizing solution comprises
the acrylamide monomer and one or more other monomers selected from
N,N'-methylene-bis-acrylamide and N,N'-ethylene-bis acrylamide.
[0036] The reactions involved in the process described above and
which lead to the formation of the cross-links in the acrylic
polymer may be schematically represented as follows: 2
[0037] The polymerizing reaction may follow one of two courses,
depending on operating conditions.
[0038] Initially, the polymer (a) under formation in the presence
of O.sub.2 forms the compound (b). At this point, the compound (b)
can form the polymer compound (c) which constitutes one possible
end product of this polymerization process.
[0039] Alternatively, the compound (b) may form the compound (a')
by elimination of NO. After forming the compound (a'), the reaction
ends with the formation of the polymer compound (b'). The "* "
symbol indicates the nitrogen atoms involved in the reaction to
eliminate NO.
[0040] The reaction involved in polymerization is the substitution
of N--O with N--C links. The (OH) is provided by the oxidation of
H--N--O. According to Hoffman, the (OH) as basic catalyst attacks
an NH.sub.2 group. The same reaction occurs in the analogous chain
and cross-link is produced.
[0041] The reaction medium may be weakly acidic or weakly alkaline.
In the former case, the polymer compound (b') is produced, the
latter case, the polymer compound (b).
[0042] As the reaction proceeds, the ketone groups may also be
attacked, transforming some of the CO into COOH.
[0043] The present invention also has for an object a cross-linked
acrylic polymer that can be prepared using the process described
above.
[0044] Another object of the present invention is to apply to the
field of medicine the cross-linked and/or, by the use of metal
salts, cross-linked chelated acrylic polymer as a material for
plastic surgery.
[0045] Advantageously, the cross-linked polymer according to the
present invention is used in surgery in endoprostheses for soft
tissue. This application is designed to increase the volume of the
soft tissue and to fill in gaps of varying sizes in such
tissue.
[0046] The cross-linked and/or (by the use of metal salts)
cross-linked chelated acrylic polymer prepared using the process
according to the present invention has the following chemical and
physical properties:
[0047] pH between 6.5 and 7.5, preferably 7;
[0048] ppm<0.2;
[0049] radiotransparent;
[0050] colourless;
[0051] oxidizing value<1;
[0052] dry residue between 3 and 4, preferably 3.5;
[0053] no free heavy metal ions within the molecule;
[0054] imide type links visible at spectrophotometer; and
[0055] insoluble in water.
[0056] Advantageously, the cross-linked and/or, by the use of metal
salts, cross-linked chelated acrylic polymer according to the
present invention takes the form of a hydrogel.
[0057] The cross-linked polymer according to the present invention
has been tested at several research centres. The tests have shown
not only the high degree of bio-compatibility of the material but
also its total incapacity to stimulate cell growth.
[0058] The chemical and physical properties of the cross-linked
polymer according to the present invention are such that it can
maintain its structural stability even in time. Once implanted, a
permanent capsule is formed which isolates the compound from the
surrounding tissue. Thanks to these properties, the cross-linked
polymer according to the present invention undoubtedly constitutes
a novelty. It can be injected into a patient's body (to form a
prosthesis endogenously) in much larger quantities than the average
quantities normally used up to now. As much as several hundred
grams of it can be implanted without risk to the patient's
health.
[0059] This biological safety has been demonstrated not only by
biological studies but also by a multicentric clinical study
conducted at several Italian universities.
[0060] The invention will now be further described with reference
to the following application examples without restricting the scope
of the inventive concept.
EXAMPLE 1
[0061] A polymerizing solution, prepared with the following
components, is placed in a reactor and agitated continuously:
[0062] 24.5 g acrylamide,
[0063] 0.025 g ethylene-bis(oxyethylene nitrilo)-tetracetic
acid,
[0064] 1.63 g of N,N'-methylene-bis-acrylamide, and
[0065] 2.5 g ammonium persulphate in 1000 ml of twice-distilled
water with a pH of 5.6.
[0066] The polymerizing solution is heated to 80.degree. C. To
obtain the polymer, oxygen is bubbled through the solution and the
solution agitated, keeping the reaction medium at a temperature of
80.degree. C. for two hours.
[0067] The product is then washed in hot water at 90.degree. C. for
four hours.
[0068] Next, the product is held at a temperature of 125.degree. C.
for five hours.
[0069] The end product is the cross-linked polymer according to the
present invention.
EXAMPLE 2
[0070] The following components are reacted in 1000 ml of
twice-distilled water:
[0071] 27.4 g acrylamide,
[0072] 0.50 g of N,N'-ethylene-bis-acrylamide,
[0073] 2.5 g ammonium persulphate, and
[0074] 0.1 g of AgNO.sub.3.
[0075] The acrylamide is reacted with N,N'-ethylene-bis-acrylamide
in the presence of ammonium persulphate. After mixing for 30
minutes, O.sub.2 is bubbled through and reacted with the silver
nitrate. The solution is left to stand for 30 minutes at 37.degree.
C. The end product has a pH of 4.8 and a dry residue of 7.2%.
EXAMPLE 3
[0076] The following components are reacted in 500 ml of apyrogenic
water:
[0077] 48 g methylolacrylamide,
[0078] 0.60 g of N,N'-methylene-bis-acrylamide,
[0079] 0.45 g of N,N'-ethylene-bis-acrylamide, and
[0080] 4 g ammonium persulphate.
[0081] The methylolacrylamide is reacted with the cross-linking
agents in the presence of ammonium persulphate for approximately 15
minutes at 37.degree. C. The oxygen is then bubbled through for 20
minutes and the solution left to stand in a warmer at 60.degree. C.
for 12 hours. The resulting product is pH 7 (and ppm<4). The
product is then washed at 90.degree. C. for 30 minutes to remove
the residual monomers.
EXAMPLE 4
[0082] The following components are reacted in 500 ml of apyrogenic
water:
[0083] 400 ml of twice-distilled water at pH 5.7,
[0084] 20 g of acrylamide,
[0085] 2 ml of hydrogen peroxide 30%, and
[0086] 0.04 g ammonium persulphate.
[0087] The above solution is placed in a reactor and agitated
continuously with oxygen bubbled through it for 16 hours at
55.degree. C. The resulting polymer is washed as in the previous
example. The polymer is then treated at 125.degree. C. for 3
hours.
EXAMPLE 5
[0088] 20 g of acrylamide, 2 ml of hydrogen peroxide 30% and 0.04 g
of ammonium persulphate are reacted in 400 ml of twice-distilled
water with pH 5.7.
[0089] The solution is placed in a reactor as in the previous
example, agitated continuously and with oxygen bubbled through it
for 16 hours at 55.degree. C.
[0090] The resulting polymer is washed as in the previous example
and treated at 125.degree. C. for 3 hours.
* * * * *